HLA allelic distribution was analysed in a cohort of 96 Northern Italian subjects (53M/43F) (mean age 59.9 ± 13.3 years) from Lombardy who developed COVID-19 during the first two pandemic waves to ...investigate possible correlations between HLA molecules and disease severity. An important role of HLA- B and HLA-C loci in modulating the clinical severity of COVID-19 disease was identified. In particular, the HLA-B07 supertype was observed to be associated with a significant risk for severe disease; conversely, the HLA-B27 supertype and
allele played a protective role as they were associated with milder disease. These associations were confirmed after applying a multinomial regression analysis to adjust the correlation for age, gender and comorbidities with COVID-19 severity. Though the power of results is limited by the small sample size, data herein contribute to shedding light on the role played by genetic background in COVID-19 infection.
We describe the case of a 54-year-old Caucasian Italian male experiencing episodes of hypoglycemia, occurring mainly after meals. He had never been exposed to insulin and was taking ramipril, ...flecainide and acetylsalicylic acid. An oral glucose tolerance test (OGTT) showed high blood glucose levels diagnostic for diabetes mellitus at 120 min and hypoglycemia with inappropriately high insulin levels at 240 min. The 72-h fasting test, abdominal computed tomography (CT) and positron emission tomography-CT were normal. Insulin autoantibodies were positive at high titers, prompting a diagnosis of insulin autoimmune syndrome (IAS). The patient was advised to take frequent, small meals and thus achieved a good control of his hypoglycemic symptoms. After 18 months of this dietary management, his insulin autoantibody levels decreased considerably but remained detectable. During an OGTT, his blood glucose levels at 120 min were now indicative of an impaired glucose tolerance rather than diabetes, and there was improvement in the glucose nadir. The patient had no other clinical or latent autoimmune diseases. Here we discuss the main features of IAS (also known as Hirata’s disease) and review the cases of IAS reported in Italy to date.
Natural killer cell-type lymphoproliferative disease of granular lymphocytes is a disorder characterized by chronic proliferation of CD3(-)CD16(+) granular lymphocytes. By flow cytometry analysis, we ...previously demonstrated a dysregulation in killer immunoglobulin-like receptor (KIR) expression in natural killer cells from patients with this lymphoproliferative disease, the activating KIR receptors being mostly expressed. We also found that patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes usually had KIR genotypes characterized by multiple activating KIR genes.
We investigated the mRNA levels of the KIR3DL1 inhibitory and the related KIR3DS1 activating receptors in 15 patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes and in ten controls. These genes are usually expressed when present in the genome of the Caucasian population.
We demonstrated the complete lack of KIR3DL1 expression in most of the patients analyzed, with the receptor being expressed in 13% of patients compared to in 90% of controls (P<0.01). Interestingly, studies of the methylation patterns of KIR3DL1 promoter showed a significantly higher methylation status (0.76 ± 0.12 SD) in patients than in healthy subjects (0.49±0.10 SD, P<0.01). The levels of expression of DNA methyl transferases, which are the enzymes responsible for DNA methylation, did not differ between patients and controls.
In this study we showed, for the first time, a consistent down-regulation of the inhibitory KIR3DL1 signal due to marked methylation of its promoter, thus suggesting that together with the increased expression of activating receptors, the lack of the inhibitory signal could also play a role in the pathogenesis of natural killer cell-type lymphoproliferative disease of granular lymphocytes.
The HLA‐DPB1 locus has been demonstrated to have a significant role on patients' outcome after allogeneic HSCT, and the so‐called T‐cell epitope (TCE) algorithm has been incorporated in international ...guidelines for the selection of unrelated donors. The purpose of the present study is to measure, through a national survey conducted on behalf of the Associazione Italiana di Immunogenetica e Biologia dei Trapianti (AIBT), the extent of awareness and use of HLA‐DPB1 TCE‐based algorithms during the donor search. 89% of the HLA laboratories answered to a short questionnaire and the results showed a progressive increase of the laboratories typing DPB1 in patients and their potential donors during the search (from 44% to 79% during the 2010–2019 period) as well as the application of a TCE‐based algorithm for the donor choice whenever possible (from 24% to 65% during the same period). The DP‐permissiveness status is detailed in the official HLA typing report by 12%, 32% and 50% of laboratories in 2010, 2015 and 2019, respectively. The present data indicate an encouraging raise in the awareness of the HLA‐DPB1 role in unrelated donor selection; noteworthy, mentioning the TCE‐based permissiveness status in the HLA typing report of each potential unrelated donor represents a notable mean to raise awareness among transplant physicians and to support them in their task of choosing the best donor. Nonetheless, despite the compelling evidence of the predictive ability of TCE‐based algorithms, further efforts are still needed to extend its application to all transplant centers in Italy.
A 61-year-old man was observed to develop type 1 diabetes mellitus following a 3-month treatment with recombinant α-2b peginterferon combined with ribavirin for chronic hepatitis C. Serum samples, ...collected before the start of therapy and 2 months after the diagnosis of diabetes mellitus, revealed islet-cell antibodies at a titer of 20 and 40 JDF–U, respectively, and glutamic acid decarboxylase autoantibodies at a value of 76.5 and 196 IU/ml, respectively. Antibodies to second islet autoantigen were persistently negative. HLA class II typing revealed the presence of DRB1*04/DRB1*14, DQA1*0303-0104 and DQB1*04-0503 alleles. Eight months after the onset of type 1 diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and serum hepatitis C virus RNA is negative. These data confirm that, in patients with potential diabetes mellitus, the disease may become manifest as a side-effect during therapy with peginterferon-α plus ribavirin. The patient as a candidate for interferon treatment should therefore be investigated, in addition to thyroid autoimmunity, also for pancreatic autoantibodies before starting therapy.
A 61-year-old man was observed to develop type 1 diabetes mellitus following a 3-month treatment with recombinant alpha-2b peginterferon combined with ribavirin for chronic hepatitis C. Serum ...samples, collected before the start of therapy and 2 months after the diagnosis of diabetes mellitus, revealed islet-cell antibodies at a titer of 20 and 40 JDF-U, respectively, and glutamic acid decarboxylase autoantibodies at a value of 76.5 and 196 IU/ml, respectively. Antibodies to second islet autoantigen were persistently negative. HLA class II typing revealed the presence of DRB1*04/DRB1*14, DQA1*0303-0104 and DQB1*04-0503 alleles. Eight months after the onset of type 1 diabetes mellitus, the patient is still receiving 30 IU insulin daily; the liver function tests are normal and serum hepatitis C virus RNA is negative. These data confirm that, in patients with potential diabetes mellitus, the disease may become manifest as a side-effect during therapy with peginterferon-alpha plus ribavirin. The patient as a candidate for interferon treatment should therefore be investigated, in addition to thyroid autoimmunity, also for pancreatic autoantibodies before starting therapy.
ObjectiveAddison's disease (AD) is a rare endocrine condition.DesignWe aimed to evaluate clinical, immunologic, adrenal imaging, and genetic features in 633 Italian patients with AD followed up since ...1967.MethodsAdrenal cortex autoantibodies, presence of other autoimmune and nonautoimmune diseases, nonadrenal autoantibodies, adrenal imaging, and genetic profile for HLA-DRB1 and AIRE were analyzed.ResultsA total of 492 (77.7%) patients were found to be affected by autoimmune AD (A-AD), 57 (9%) tuberculous AD, 29 (4.6%) genetic-associated AD, 10 (1.6%) adrenal cancer, six (0.94%) post-surgical AD, four (0.6%) vascular disorder-related AD, three (0.5%) post-infectious AD, and 32 (5.1%) were defined as idiopathic. Adrenal cortex antibodies were detected in the vast majority (88–100%) of patients with recent onset A-AD, but in none of those with nonautoimmune AD. Adrenal imaging revealed normal/atrophic glands in all A-AD patients: 88% of patients with A-AD had other clinical or subclinical autoimmune diseases or were positive for nonadrenal autoantibodies.Based on the coexistence of other autoimmune disorders, 65.6% of patients with A-AD were found to have type 2 autoimmune polyendocrine syndrome (APS2), 14.4% have APS1, and 8.5% have APS4. Class II HLA alleles DRB1*03 and DRB1*04 were increased, and DRB1*01, DRB1*07, DRB1*013 were reduced in APS2 patients when compared with controls. Of the patients with APS1, 96% were revealed to have AIRE gene mutations.ConclusionsA-AD is the most prevalent form of adrenal insufficiency in Italy, and ∼90% of the patients are adrenal autoantibody-positive at the onset. Assessment of patients with A-AD for the presence of other autoimmune diseases should be helpful in monitoring and diagnosing APS types 1, 2, or 4 and improving patients' care.
Abstract Humoral immune mechanisms may have a role in the neurological complications of celiac disease (CD). We assessed 71 CD patients for neurologic manifestations and presence of serum antibodies ...to neural antigens. Sixteen patients (22.5%) were found to have neurological deficits including headache, depression, entrapment syndromes, peripheral neuropathy, and epilepsy. Antibody reactivity to neural antigens was detected in 30/71 (42.2%) patients. There was no clear correlation between anti-neural reactivity and neurologic dysfunction. Follow-up of 62 patients did not reveal change in electrophysiology or antibodies, regardless of diet. However, in 2 patients with neuropathy, symptoms improved or worsened depending on the diet.
Summary
Objective To assess autoimmune regulator (AIRE) gene mutations, class II HLA haplotypes, and organ‐ or non‐organ‐specific autoantibodies in patients with chronic hypoparathyroidism (CH) ...without associated Addison’s disease (AD) or chronic candidiasis (CC).
Design, Patients and Measurements Twenty‐four patients who had CH without AD or CC were included in the study. AIRE gene mutations in all 14 exons were studied using PCR in 24 patients, 105 healthy controls and 15 first‐degree relatives of CH patients with AIRE mutations. Human leucocyte antigens (HLA) were determined for all 24 patients and 105 healthy controls. Autoantibodies to a range of antigens including NACHT leucine‐rich‐repeat protein‐5 (NALP5) and interferon omega (IFNω) were tested in all 24 patients.
Results AIRE gene mutations were found in 6 of 24 (25%) patients, all females, and this was significantly higher (P < 0·001) compared with AIRE mutations found in healthy controls (2/105). Three patients (12·5%) had homozygous AIRE mutations characteristic of Autoimmune‐Poly‐Endocrinopathy‐Candidiasis‐Ectodermal‐Dystrophy and all three were also positive for IFNω‐autoantibodies. Three patients (12·5%) had heterozygous AIRE mutations; two of these were novel mutations. One of the patients with heterozygous AIRE mutations was positive for both NACHT leucine–rich‐repeat protein 5 and IFNω autoantibodies. Heterozygous AIRE mutations were found in 10 of 15 first‐degree relatives of CH patients with AIRE mutations, although none was affected by CH. Class II HLA haplotypes were not statistically different in patients with CH compared to healthy controls.
Conclusions Analysis of AIRE gene mutations together with serum autoantibody profile should be helpful in the assessment of patients with CH, in particular young women with associated autoimmune diseases.
An autoimmune background is thought to characterize the families of multiple sclerosis (MS) patients, but disease patterns and HLA-DR association seem to vary considerably among different ethnic ...groups. We investigated the prevalence of autoimmune diseases in 245 MS patients and 245 age- and sex-matched normal controls (NC), originating from and living in North-east Italy, and their first degree relatives, using a case-control method. Further, HLA-DRB1 expression was analysed in MS and NC. The following significant findings were observed: 1) a significant excess of autoimmunity in first-degree relatives of MS patients (p = 0.000), 2) an association of MS with Type 1 diabetes mellitus (T1DM) (p = 0.02), 3) an increase in DR4 expression (namely DRB1*0401) in MS patients from families with multiple autoimmune pathology compared with reference MS patients (p=0.02) and NC (p=0.01). We conclude that the risk of autoimmune disease is higher in first-degree relatives of MS patients and that disease association and HLA-DR expression in North-east Italy differs from other geographic regions of Europe.
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